This proposal is to request support for a Keystone Symposia meeting entitled Towards Defining the Pathophysiology of Autistic Behavior, organized by Pat Levitt and Joseph Piven, which will be held in Snowbird, Utah from April 11 - 15, 2010. Autism is a neurodevelopmental disorder defined by the co- occurrence of a set of characteristic behavioral features. One of the most common neurodevelopmental disorders, autism is recognized as heterogeneous in etiology, phenotype, behavioral trajectory and response to treatment. While the etiology and specific pathogenetic mechanisms underlying autism are unknown, those mechanisms which underlie a small subset of etiologically-defined neurodevelopmental disorders (e.g., Fragile X Syndrome, tuberous sclerosis), that are associated with autism and autistic behaviors, have been well described. The overarching aim of this Keystone Symposia meeting will be to take advantage of our knowledge of etiologic heterogeneity by examining the phenomenology and pathophysiology of etiologically- defined autistic syndromes, and contrasting this with what is known about idiopathic autism, in order to ultimately shape the development of treatment approaches informed by knowledge of the underlying pathophysiology. This conference will bring together clinical and basic scientists from various disciplines to expand on the success of an earlier Keystone Symposia meeting on this topic by additionally: 1) covering a broader number of etiologically-defined autistic syndromes;2) comparing and contrasting the phenomenology (including physical features, behavior and neural circuitry) of autistic syndromes, to refine ideas regarding etiologically- meaningful aspects of the autism phenotype;3) examining the role of the environment (epigenetic influences) in contributing to the etiology and underlying mechanisms of autism (including idiopathic autism and autistic syndromes), with the aim of elucidating a more comprehensive understanding of the pathophysiology of autistic behavior;and 4) examining how gene-by-environment (GxE) factors impact synaptic function and plasticity that may lie at the heart of autism syndromes. Moreover, the pairing of this meeting with the meeting entitled Synapses: Formation, Function and Misfunction provides unique opportunities for high-level interdisciplinary interactions that are likely to lead to new directions in research. PUBLIC HEALTH RELEVANCE: Autism Spectrum Disorders (ASD), affecting 1 in 150 individuals, is a group of heterogenous disorders that can range from having severe to mild impacts on children and adult social behavior and communication, with typical restricted interests, repetitive behavior and challenges in emotional regulation. The overarching aim of the Autism conference will be to promote a dialogue between clinical, translational and basic scientists from a wide variety of areas to identify common themes that will help better understand the pathogenesis of ASD and, most important, to promote new research directions and possible treatments.